Establishing a Dose-response Relationship With Accelerated Transcranial Magnetic Stimulation

NCT04243798 | Completed Results DMC FDA Device

• 1 other identifier: 54909
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

This study evaluates an accelerated schedule of theta-burst stimulation using a transcranial magnetic stimulation device for treatment-resistant depression. In a double-blind, randomized, sham-controlled fashion, half the participants will receive accelerated theta-burst stimulation while half will receive sham treatment.

Conditions

Treatment Resistant Depression

Keywords

transcranial magnetic stimulation; theta burst

Outcome Measures

Primary Outcomes (1)

• Change in Resting State Functional Connectivity of the Subgenual Anterior Cingulate Cortex (sgACC) and the Default Mode Network (DMN).

  Assessment of functional connectivity of sgACC to the DMN using magnetic resonance imaging.

  Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 3), Visit 6 (Day 4), Visit 7 (Day 5) and Immediate Post Treatment Follow Up (Visit 8 and Day 6)

Secondary Outcomes (2)

• Relationship Between Clinical Improvement and Resting State Functional Connectivity Between the sgACC and DMN in Active vs. Sham Participants.

  Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 3), Visit 6 (Day 4), Visit 7 (Day 5) and Immediate Post Treatment Follow Up (Visit 8/Day 6))

• Relationship Between Acute Mood State and Resting State Functional Connectivity Between the sgACC and DMN in Active vs. Sham Participants.

  Visit 3 (Day 1), Visit 4 (Day 2), Visit 5 (Day 3), Visit 6 (Day 4), Visit 7 (Day 5) and Immediate Post Treatment Follow Up (Visit 8/Day 6))

Study Arms (2)

Active TBS-DLPFC

EXPERIMENTAL

The active group will receive theta-burst TMS stimulation.

Device: Active TBS-DLPFC

Sham TBS-DLPFC

SHAM COMPARATOR

The sham group will receive sham theta-burst TMS stimulation.

Device: Sham TBS-DLPFC

Interventions

Active TBS-DLPFC DEVICE

Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro x100 TMS system (MagVenture, Denmark).

Active TBS-DLPFC

Sham TBS-DLPFC DEVICE

The parameters in the sham arm will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.

Sham TBS-DLPFC

Eligibility Criteria

• Age: 22 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or Female, between the ages of 22 and 65 at the time of screening.
• Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS interventions. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information.
• Currently diagnosed with Major Depressive Disorder (MDD) and meets criteria for a Major Depressive Episode, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5).
• Medical records confirming a history of moderate to severe treatment-resistance as defined by a score of 7-14 on the Maudsley Staging Method (MSM3).
• MADRS score of ≥20 at screening (Visit 1).
• TMS naive.
• Access to ongoing psychiatric care before and after completion of the study.
• Access to clinical rTMS after study completion.
• Must be on a stable antidepressant therapeutic regimen for 6 weeks prior to study enrollment and agree to continue this regimen throughout the study period.
• In good general health, as evidenced by medical history.
• For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
• Agreement to adhere to Lifestyle Considerations throughout study duration.
• Lifestyle considerations:
• Abstain from becoming pregnant from the screening visit (Visit 1) until after the final study visit (Visit 9).
• Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) without significant change for the duration of the study.

You may not qualify if:

• Pregnancy
• Primary psychiatric condition other than MDD requiring treatment except stable comorbid anxiety disorder
• History of or current psychotic disorder or bipolar disorder
• Severe borderline personality disorder.
• Diagnosis of Intellectual Disability or Autism Spectrum Disorder
• Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
• Urine screening test positive for illicit substances
• Active suicidal ideation (defined as an MSSI \> 8) or a suicide attempt (as defined by the C-SSRS) within the past one year
• Any history of ECT (greater than 8 sessions) without meeting responder criteria
• Recent (within 4 weeks of any clinical effect) or concurrent use of rapid acting antidepressant agent (i.e., ketamine or a course of ECT)
• History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma
• Untreated or insufficiently treated endocrine disorder.
• Contraindication to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion)
• Contraindication to MRI (ferromagnetic metal in their body)
• Treatment with another investigational drug or other intervention within the study period

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine

Stanford, California, 94305, United States

Location

Related Publications (16)

• George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE 3rd, Schwartz T, Sackeim HA. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010 May;67(5):507-16. doi: 10.1001/archgenpsychiatry.2010.46.

  PMID: 20439832 BACKGROUND

• George MS, Wassermann EM, Williams WA, Callahan A, Ketter TA, Basser P, Hallett M, Post RM. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995 Oct 2;6(14):1853-6. doi: 10.1097/00001756-199510020-00008.

  PMID: 8547583 BACKGROUND

• Pascual-Leone A, Rubio B, Pallardo F, Catala MD. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. 1996 Jul 27;348(9022):233-7. doi: 10.1016/s0140-6736(96)01219-6.

  PMID: 8684201 BACKGROUND

• Chung SW, Hill AT, Rogasch NC, Hoy KE, Fitzgerald PB. Use of theta-burst stimulation in changing excitability of motor cortex: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2016 Apr;63:43-64. doi: 10.1016/j.neubiorev.2016.01.008. Epub 2016 Feb 3.

  PMID: 26850210 BACKGROUND

• Jelic MB, Milanovic SD, Filipovic SR. Differential effects of facilitatory and inhibitory theta burst stimulation of the primary motor cortex on motor learning. Clin Neurophysiol. 2015 May;126(5):1016-23. doi: 10.1016/j.clinph.2014.09.003. Epub 2014 Sep 16.

  PMID: 25281475 BACKGROUND

• Chung SW, Hoy KE, Fitzgerald PB. Theta-burst stimulation: a new form of TMS treatment for depression? Depress Anxiety. 2015 Mar;32(3):182-92. doi: 10.1002/da.22335. Epub 2014 Nov 28.

  PMID: 25450537 BACKGROUND

• Plewnia C, Pasqualetti P, Grosse S, Schlipf S, Wasserka B, Zwissler B, Fallgatter A. Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J Affect Disord. 2014 Mar;156:219-23. doi: 10.1016/j.jad.2013.12.025. Epub 2013 Dec 28.

  PMID: 24411682 BACKGROUND

• Prasser J, Schecklmann M, Poeppl TB, Frank E, Kreuzer PM, Hajak G, Rupprecht R, Landgrebe M, Langguth B. Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. World J Biol Psychiatry. 2015 Jan;16(1):57-65. doi: 10.3109/15622975.2014.964768. Epub 2014 Nov 28.

  PMID: 25430687 BACKGROUND

• Daskalakis ZJ. Theta-burst transcranial magnetic stimulation in depression: when less may be more. Brain. 2014 Jul;137(Pt 7):1860-2. doi: 10.1093/brain/awu123. Epub 2014 May 15. No abstract available.

  PMID: 24833712 BACKGROUND

• Thut G, Pascual-Leone A. A review of combined TMS-EEG studies to characterize lasting effects of repetitive TMS and assess their usefulness in cognitive and clinical neuroscience. Brain Topogr. 2010 Jan;22(4):219-32. doi: 10.1007/s10548-009-0115-4. Epub 2009 Oct 28.

  PMID: 19862614 BACKGROUND

• Holtzheimer PE 3rd, McDonald WM, Mufti M, Kelley ME, Quinn S, Corso G, Epstein CM. Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Depress Anxiety. 2010 Oct;27(10):960-3. doi: 10.1002/da.20731.

  PMID: 20734360 BACKGROUND

• Fung PK, Robinson PA. Neural field theory of synaptic metaplasticity with applications to theta burst stimulation. J Theor Biol. 2014 Jan 7;340:164-76. doi: 10.1016/j.jtbi.2013.09.021. Epub 2013 Sep 21.

  PMID: 24060620 BACKGROUND

• Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med. 1995 Oct;34(4):537-41. doi: 10.1002/mrm.1910340409.

  PMID: 8524021 BACKGROUND

• Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):253-8. doi: 10.1073/pnas.0135058100. Epub 2002 Dec 27.

  PMID: 12506194 BACKGROUND

• Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9673-8. doi: 10.1073/pnas.0504136102. Epub 2005 Jun 23.

  PMID: 15976020 BACKGROUND

• Greicius MD, Supekar K, Menon V, Dougherty RF. Resting-state functional connectivity reflects structural connectivity in the default mode network. Cereb Cortex. 2009 Jan;19(1):72-8. doi: 10.1093/cercor/bhn059. Epub 2008 Apr 9.

  PMID: 18403396 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Results Point of Contact

• Title: Principal Investigator
• Organization: Stanford University

nbassano@stanford.edu

650-736-2233

Study Officials

• David Spiegel, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Department of Psychiatry and Behavioral Sciences, Stanford University

Study Record Dates

• First Submitted: January 25, 2020
• First Posted: January 28, 2020
• Study Start: June 15, 2021
• Primary Completion: June 21, 2024
• Study Completion: June 21, 2024
• Last Updated: March 30, 2026
• Results First Posted: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)